tbuckley/cabot-search huggingface dataset:
B-TREUH results: A single-arm phase II pilot study of euthyroid hypothyroxinemia in metastatic breast carcinoma.
Authors: Shruti Trehan, Suzan S. Cheng, Anisha Rawal, Mary Amos, Kathleen Collins, Aleck Hercbergs
Journal: Journal of Clinical Oncology (2023)

e13111 Background: Thyroid abnormalities are prevalent in up to 1/3 breast cancer patients. T4/L-thyroxine is the most commonly prescribed treatment for hypothyroidism. However, T4 has been shown to be a potent pro-oncogenic agent by stimulating mitogenesis and angiogenesis, and inhibiting apoptosis, anti-PDL-1 and radiation effects. T3/triiodothyronine is significantly less oncogenic and mitogenic. Hence, using T3 rather than T4 might have anti-oncogenic effects, resulting in slower disease progression and improved outcomes. Methods: Adults with metastatic breast carcinoma on active treatment with estimated life expectancy of &gt; 3months and hypothyroidism on T4 and normal TSH were eligible. Following informed consent, participants discontinued T4 and initiated T3 after a washout period. T3 dosing and titration was based on their previous dose of T4 and thyroid function testing to maintain levels of free T4 at &lt; 50% normal range. The treatment period was 9 months and follow up for 12 months. The primary endpoint was progression free survival. Secondary endpoints were prevalence of hypothyroidism in the cohort, overall survival, quality of life, and time to achieve euthyroid hypothyroxinemia. Results: The trial was terminated early due to the pandemic and relocation of the PI and Sub-I. 7 female patients from a community medical oncology practice were enrolled between March 2019 and March 2022, Duration of metastatic breast cancer 7-223 months (average 62 months). Progression-free survival at 9 months was 5/7 (71%). Progression free survival (PFS) at 12 months, calculated in 6 patients due to data cut-off deadline and premature study closure, was 4/6 (67%). Overall survival at 9 months was 6/7 (85%). 1 patient died due to disease progression. The prevalence of hypothyroidism was 26/126 (21%). Euthyroid hypothyroxinemia was achieved in 100%, in average time of 59.6 days. 0% of the 14 serious adverse events were attributed to T3. Quality of life FACT-B scores on T4 vs T3 were not statistically significant. Conclusions: B-TREUH is the first prospective trial of euthyroid hypothyroxinemia in hypothyroid metastatic breast cancer. The transition from T4 to T3 was well tolerated with no serious adverse side effects or on quality of life. In this heavily pretreated population, PFS was 71% at 9 months and 67% at 12 months. The small number and heterogeneity of this cohort make interpretation of the PFS challenging. This unique study is simple yet provocative. Larger, broader studies are needed to explore this concept further. The low cost and easy availability of T3 and high prevalence of hypothyroidism make it an exceptionally attractive agent for future oncology research. Clinical trial information: NCT03787303 .
Phase II randomized window of opportunity trial evaluating cytotoxic and immunomodulatory effects of intratumoral INT230-6 in early stage breast cancer: The INVINCIBLE trial.
Authors: Melanie Spears, Megan Hopkins, Kianoosh Keyhanian, Susan Robertson, Linda Liao, Vida Talebian, Arif Ali Awan, Gregory Russell Pond, John Bartlett, Lewis H. Bender, Ian B. Walters, Vanessa Lopez-Ozuna, Angel Arnaout
Journal: Journal of Clinical Oncology (2023)

573 Background: Most breast cancers are considered immunological cold and are therefore minimally responsive to immunotherapies. Local cytotoxic therapies can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. We conducted a randomized, double blind, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trialNCT04781725. The trial evaluated the immune response within the tumor and microenvironment in vivo after IT INT230-6 injections. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade ER+ T1-T2 invasive breast cancers were recruited to the trial. Participating patients were allocated (2:1) to IT injections of INT230-6 vs saline placebo, prior to resection. RNA profiling of the pre- (baseline biopsy) and post- treatment (surgical resection) tumours using the Ion AmpliSeq Transcriptome Human Gene Expression (Thermo Fisher Scientific) and DNA sequencing using a large (500 gene) comprehensive genomic profiling panel (OCAPlus,) was performed. Results: Significant tumor necrosis was observed in the majority of subjects injected with INT230-6. In the 60 pre-treatment biopsies profiled with OCAPlus, the genes most frequently mutated included PIK3CA (38%), TP53 (23%), CDH1 (22%) and TBX3 (17%). Frequent copy number changes were identified in CCND1 (23%), FGFR1 (18%), and CDH1 (17%). Gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens in patients treated with the drug. Pathway analysis identified genes associated with TCR signaling, macrophage markers, IL-18 signaling and B cell receptor signaling were significantly up-regulated in the post treatment samples. Conclusions: This is the first study evaluating the potential biologic effects of intratumoral cytotoxicity with INT230-6 and its role as a potential immune priming therapy in traditional immune quiescent ER+ breast cancers.
Systematic review of breast implant associated squamous cell carcinoma.
Authors: Sujan Niraula, Anjan Katel, Amit Barua, Anna Weiss, Myla S. Strawderman, Huina Zhang, Oscar Manrique, Avice O'Connell, Sirish Raj Pandey, Ajay Dhakal
Journal: Journal of Clinical Oncology (2023)

e12508 Background: Breast augmentation is a cosmetic procedure with low rates of complication like bleeding, infection, implant rupture, and capsular contracture. However, rare cases of breast implant-associated (BIA) malignancies, including anaplastic large cell lymphoma (ALCL) and squamous cell carcinoma (SCC), have been reported. BIA-SCC is rarer than ALCL and current literature is limited to case reports. In 2022, the American Society of Plastic Surgeons (ASPS) issued a BIA-SCC summary statement based on 16 reported cases in response to an FDA safety communication. The aim of this study is to review published cases of BIA-SCC and present clinical and outcome data systematically. Methods: We conducted a literature search in English to identify studies reporting BIA-SCC from inception to October 2022. Patient characteristics and relevant outcomes were gathered from the studies. The mortality rates at 6 and 12 months were calculated as the inverse of the Kaplan-Meier survival estimate and presented with a 95% confidence interval (CI). Results: 14 articles and 18 cases of BIA-SCC were identified through a literature search. A rising trend in case reporting was observed, with 4 cases in the 1990s and 14 cases since 2010. The mean patient age was 56 years (range 40-81), and the mean time from breast augmentation to symptom appearance was 21 years (range 10-35). Most patients (13/18, 72%) underwent the procedure for cosmetic reasons. Out of 17 cases with available implant information, 11 cases had silicone based implants and 6 cases saline implants. Implant surface information was available in 5 cases, 4 smooth and 1 textured. 16 patients had swelling of the breast and 15 patients had breast pain at presentation of BIA-SCC. All patients had their implants removed and 10 underwent mastectomy after a diagnosis of SCC. Of the 12 cases with available treatment information, 7 received adjuvant chemotherapy and/or radiotherapy, 2 received neoadjuvant chemotherapy, and 3 did not receive perioperative chemotherapy or radiotherapy. Follow-up data was available for 10 cases. The 6-month and 12-month mortality rates were 11.1% (95% CI: 0.5% to 40.6%) and 23.8% (95% CI: 2.8% to 56.1%). Conclusions: The estimated 6-month mortality rate of 11% (95% CI: 0.5%-40.6%) should be interpreted cautiously due to the small sample size. It is lower than the rate reported by ASPS (44%), but the reason for this difference cannot be accurately explained as the methodology for determining then mortality rate is not provided in the ASPS statement. This study provides a valuable systematic review of a rare and poorly understood condition with a poor prognosis. Monitoring and sharing information is crucial to improve detection and management of BIA-SCC. [Table: see text]
Telemedicine-supervised cancer therapy for patients with an aggressive lymphoma and metastatic lung cancer in the U.S. Veterans Affairs National TeleOncology Service.
Authors: Chenyu Lin, Katherine I. Zhou, Zachary R. Burningham, Kerry G. Rowe, Tori Anglin-Foote, Mark Maddox, Daphne Ruth Friedman, Ahmad Sami Halwani, Vida Almario Passero, Michael J. Kelley, Thomas David Rodgers
Journal: Journal of Clinical Oncology (2023)

1602 Background: Telemedicine is increasingly used in cancer care but has mostly been applied to surveillance and oral therapy rather than parenteral treatments. In the U.S. Veterans Affairs National TeleOncology service (NTO), patients receive intravenous cancer treatments locally under remote supervision from a disease-specialized oncologist. We analyzed care delivered by the NTO for patients with an aggressive lymphoma (AL) and metastatic lung cancer (mLC). Methods: The demographics of veterans with AL and mLC enrolled in NTO between 2020-2023 were compared to patients receiving in-person care at the VA. From these NTO cohorts, two subsets of patients receiving 1 st line therapy for diffuse large B cell lymphoma (DLBCL) and stage IV non-small cell lung cancer (NSCLC) were extracted and compared to control arms of in-person care matched 1:4 by stage, age, PDL1 (NSCLC), and cytogenetics (DLBCL). Fisher’s exact test was used for categorical variables, t test for continuous variables, log rank for survival, and negative binomial for count outcomes. Results: 140 patients with AL or mLC (40 DLBCL, 13 Hodgkin, 2 Burkitt, 61 NSCLC, 24 SCLC) were enrolled in NTO, spanning 12 U.S. states. Compared to in-person care ( n = 7,561), NTO had more rural (56% vs. 34%, p &lt; 0.001) and white patients (89% vs. 77%, p = 0.002). With a median follow-up of 256 days (IQR, 154 - 415), NTO mLC and AL patients had a median of 15 and 17 telemedicine visits, respectively. 13 of 55 AL (24%) and 56 of 85 mLC (66%) patients received systemic therapy of any line, while 38 (69%) of AL were on surveillance. 7 mLC and 2 AL patients were referred externally for care. 11 patients with DLBCL and 30 patients with stage IV NSCLC started 1 st line therapy while in NTO, which were compared to matched controls. NTO and matched control had similar mean time from referral to first appointment and from diagnosis to first treatment. There were no significant differences in progression-free survival between NTO and matched controls for NSCLC (HR 1.1, 95% CI 0.7-1.8) or DLBCL (HR 0.5, 95% CI 0.1-2.3). COVID infections in the first 12 months and number of ED visits in the first 3 months of treatment were not statistically different from controls. Conclusions: The NTO service demonstrates the feasibility of infusional chemoimmunotherapy administration under the direction of a remote tele-oncologist. This model has the potential to improve access to specialized oncology care for rural populations and provides a framework for decentralized clinical trials.[Table: see text]
Survival-inferred fragility index of FDA-approved cancer drugs using surrogate endpoints.
Authors: Jonathan Ofer, Shai Gilboa, Yarden Pras, Gal Markel, David Bomze, Tomer Meirson
Journal: Journal of Clinical Oncology (2023)

1573 Background: The survival-inferred fragility index (SIFI) quantifies the robustness of positive trials by estimating the number of changes in a survival analysis that would render the results insignificant. Here, we use a variation of SIFI (SIFI-median) in which the median patient is reassigned between study groups until significance is lost. Our goal was to study the robustness of oncology randomized controlled trials (RCTs) leading to drug approval by the FDA based on surrogate time-to-event endpoints. Methods: In this cross-sectional study, we identified phase II-III RCTs between 2010 and 2020. We reconstructed individual patient data from published Kaplan-Meier plots of surrogate time-to-event endpoints and calculated the SIFI-median, i.e., the minimum number of median survivor reassignments from the intervention group to the control group that would cause the loss of statistical significance. Results: A total of 101 studies comprising 60697 patients met the inclusion criteria. The most common surrogate endpoint was PFS 86 (85.1%), followed by DFS 7 (6.9%). The SIFI-median was 23 (interquartile range [IQR], 12 to 37) and the SIFI-median as a proportion of sample size was 5.3% (IQR, 2.7% to 8.1%). Forty-five studies (44.5%) had SIFI-median less than 5% of the total sample size which was often less than the number of censored patients during early follow-up. The SIFI-median was less than 1% of the total sample size in 10 studies (9.9%). Conclusions: Low fragility indices indicates that the statistical conclusions of clinical studies could be reversed with a small number of variations. The lack of statistical robustness in multiple FDA-approved drugs suggests higher uncertainty in their clinical benefit.
ECOG-ACRIN E2197: Comparison of HER2 gene expression by RT-PCR across all HER2 immunohistochemistry groups with recurrence analysis.
Authors: Nhu Thuy Can, John Bennett, Cynthia A. Flannery, Helen Bailey, Lori J. Goldstein, Nancy E. Davidson, Joseph A. Sparano, Frederick L. Baehner, Sunil S. Badve
Journal: Journal of Clinical Oncology (2023)

515 Background: Accurate assessment of HER2-low [immunohistochemical (IHC) score of 1+ or 2+ and in-situ hybridization negative] breast cancer is clinically relevant following DESTINY-Breast04. In hormone receptor positive breast cancers, Oncotype DX assay Recurrence Score results are widely used to guide adjuvant chemotherapy selection, and standardized quantitative HER2 mRNA reference-normalized expression levels by RT-PCR are included in patient reports. Previously, a high degree of concordance between central IHC and quantitative HER2 by RT-PCR was demonstrated in E2197. Here, we compare quantitative HER2 gene expression using Oncotype DX assay within all IHC subgroups and risk of recurrence in E2197. Methods: Data analyzed were from a case-control sample from E2197 (no adjuvant anti-HER2 therapy) of 755 patients. Central IHC for HER2 used duplicate 1.0 mm microarrays (HercepTest, Dako) and scored per 2007 ASCO/CAP guidelines. Based on quantitative reference-normalized RT-PCR measures of HER2 expression, cases were assigned: positive ≥11.5 units, equivocal ≥10.7 to &lt;11.5 units, and negative &lt;10.7 units (1 unit increase represents ~2-fold increase in RNA). Spearman’s rank correlation was used to measure strength of association between the 2 methods. Cox proportional hazards regression was used to evaluate the association between quantitative HER2 expression and recurrence (defined as invasive breast cancer in local, regional, or distant sites). Analyses were weighted to account for study design. Results: 48% were IHC 0, 11% were IHC 1+, 23% were IHC 2+, and 18% were IHC 3+. 85% were HER2 negative, 3% equivocal, and 11% positive by RT-PCR. While there was moderately strong correlation between HER2 IHC and HER2 gene expression by RT-PCR [Spearman’s rho: 0.63 (95% CI: 0.59, 0.67); p&lt;0.001], there were wide and overlapping ranges of HER2 gene expression across all IHC categories with almost identical medians and inter-quartile ranges for HER2 IHC 1+ and 2+ (n=248; see table). An exploratory analysis showed 86% of IHC 0, 97% of IHC 1+, and 99% of IHC 2+ had HER2 &gt;8 units. After controlling for baseline clinicopathologic features (age, hormone receptor status, grade, size, and nodal status), continuous quantitative HER2 expression was associated with time to recurrence in HER2 IHC 0 to 2+ [HR 1.17 per 1-unit increase in HER2 (95% CI 1.01, 1.35; p=0.036)]. Conclusions: There was a wide range of quantitative HER2 gene expression using Oncotype DX assay across all IHC categories; continuous HER2 expression is independently associated with recurrence. Quantitative HER2 expression may be useful for identification of HER2-low breast cancer. Further studies are needed. [Table: see text]
Commercial next generation sequencing in a real-world cohort of patients with metastatic breast cancer.
Authors: Kamil Taneja, Jules A. Cohen
Journal: Journal of Clinical Oncology (2023)

e13082 Background: Clinicians increasingly order next generation sequencing (NGS) of tissue or liquid (ctDNA) biopsies from patients with metastatic breast cancer. Although some genetic information is clinically actionable, some, particularly non-ERBB2 gene amplifications, is not. We reviewed NGS data from a real-world cohort of metastatic breast cancer patients to evaluate the prevalence of somatic abnormalities using commercial NGS technology. Methods: We evaluated Foundation One NGS data from 44 tissue and 17 liquid biopsies from patients seen in a medical oncology practice between 2016 and 2022. We used KM Plotter to measure overall survival in early-stage patients by relative gene expression. Results: 76% of patients had ductal and 24% had lobular carcinomas. 59% of patients had luminal (ER-positive) and 32% of patients had basal breast cancer (ER-negative). Only 9% of patients had HER2-positive disease. 48% of the tumors had a p53 abnormality, either a point (59%) or frameshift mutation (36%). 50% tumors had a somatic mutation in a tumor suppressor gene such as PTEN, RB or APC. One patient had a germline BRCA1 mutation and 5 patients had germline BRCA2 mutations. 39% of patients carried a somatic mutation in PIK3CA, predominantly H1047R (45%) in the kinase domain or E545X (20%) in the helicase domain. KM plotter showed worse OS in early-stage patients with low p53 gene expression or high PIK3CA expression. 10/11 patients with lobular carcinoma had somatic mutations in CDH1, 70% of which were frameshift mutations. 8/27 patients with luminal cancer had an ESR1 mutation, predominantly Y537 or D538. 9 patients, predominantly luminal, had amplifications of the 11q13 (CCND1). 7 patients had amplifications of 8q24 (MYC). 20q13 (AURKA) amplifications were only seen in luminal cancers. 12p13 (CCND2) amplifications were only seen in basal cancers. 27% of lobular cancers (vs. 6-17% of ductal cancers) demonstrated amplification of the 11q13, 8q24 and/or 8p11 amplicons. 20q13 and 12p13 amplifications were only seen in ductal cancers. Liquid biopsies were more likely to detect point mutations than tissue biopsies. p53 mutations were seen in 65% of liquid vs. 48% of tissue biopsies. 47% of liquid biopsies showed two p53 mutations. PIK3CA mutations were seen in 71% of liquid vs. 39% of tissue biopsies. 18% of liquid biopsies showed two PIK3CA mutations. 93% of basal cancers had at least one p53 mutation. 44% of luminal cancers had a PIK3CA mutation. ESR1, GATA3 and AKT1 mutations were only seen in luminal cancers. While ESR1 mutations were seen in ductal and lobular cancers, GATA3 and AKT1 mutations were only seen in ductal cancers. Conclusions: Commercial NGS testing of a real-world cohort yields actionable mutations that can impact clinical management and outcome of metastatic breast cancer patients. NGS testing demonstrates the range of gene amplifications and corresponds closely with what has been reported in the published literature.
Metastatic breast cancer (MBC) with ultra-high tumor mutational burden (UHTMB): A comprehensive genomic profiling (CGP) study.
Authors: Kristina Fanucci, Maryam B. Lustberg, Neal A. Fischbach, Maureen Pelletier, Abirami Sivapiragasam, Prashanth Ashok Kumar, Mansi Kallem, Natalie Danziger, Ethan Sokol, Smruthy Sivakumar, Dean C. Pavlick, Jeffrey S. Ross, Lajos Pusztai
Journal: Journal of Clinical Oncology (2023)

1036 Background: Pts with MBC whose tumors feature high TMB (≥ 10 mutations/Mb) are eligible for on label immune checkpoint inhibitor (ICI) treatment. This study evaluated the genomic landscape of MBC with “Ultra high” TMB, defined at &gt; 20 mutations/Mb. Methods: 2049 MBC underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA), TMB, microsatellite instability (MSI) and trinucleotide mutational signatures. HER2 IHC results were available in a subset of pts. PD-L1 expression on immunocytes was determined by IHC (Ventana SP142). Results: 45/2049 (2.2%) of MBC were UHTMB. 45 (100%) pts had metastatic disease. 38 (84%) had documented Stage IV disease and 7 documented axillary LN metastases at the time of sequencing. Local breast tumor was used for CGP in 19 (42.2%) MBC and metastatic site biopsy was used in 26 (57.8%). When compared with 2004 non-UHTMB pts with UHTMB were older (mean 64.6 yrs vs 58.2 yrs p &lt; .0001), more often had lobular histology (40.0% vs 14.5% p &lt; .0001) and ER+ disease (86.6% vs 70.0%). Of the 35 UHTMB cases with HER2 IHC data available, 11 (31.4%%) were HER2 IHC negative (0+), 21 (60.0%) were HER2-low status (9 1+ and 12 2+/ISH negative) and 3 (8.6%) were HER2 IHC positive (3+). 1/3 HER2 IHC2+ cases and 2/45 (4.4%) of all UHTMB cases were positive for HER2 copy number gain on CGP. UHTMB cases had more driver GA/tumor (mean 9.8 vs 5.7 p &lt; .0001) and were less often TNBC (13.3% vs 27.0% p = .041) compared to non-UHTMB high cancers. Mutation signature analysis revealed APOBEC was predominant in UHTMB samples (82.5%); MMR signature was also observed in 10% of cases. MSI high status was significantly more frequent in UHTMB high cases (11.6% vs 0.4% p &lt; .0001). GA more frequently identified in UHTMB cases included CDH1 (45.5% vs 14.3% p &lt; .0001), PIK3CA (81.8% vs 37.9% p &lt; .0001), CDKN2A (11.4% vs 3.2% p = .017), ARID1A (25.0% vs 5.0% p &lt; .0001) and NF1 (20.5% vs 5.9% p = .0014). PD-L1 ( CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different among groups. Conclusions: UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. [Table: see text]